Epidemiological studies strongly indicate that diabetes mellitus (DM) is an independent risk factor for both mortality and morbidity following myocardial infarction (MI), especially since post-MI left ventricular function is significantly worse in DM patients. However, what is lacking is a plausible relationship between diabetes and any of the known regulators of cardiomyocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Our group has demonstrated that down-regulation of phosphodiesterase 3A (PDE3A) is associated with apoptosis and induction of inducible cAMP early repressor (ICER), a proapoptotic transcriptional repressor, providing a mechanistic framework for how angiotensin II (Ang II) regulates myocyte apoptosis. We also showed that ERK5 activation induced by cardiac specific overexpression of CA- MEK51 (constitutively active form of MEK51) in transgenic mice (Tg) inhibited ICER induction and myocyte apoptosis in DM mice after myocardial infarction (DM + MI), but the mechanism between ERK5 and ICER reduction remains unknown. Our preliminary data show that extracellular signal regulated protein kinase 5 (ERK5) and the chaperone-dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) are important in regulating heart damage after myocardial infarction in diabetes. ERK5 activation has a strong cardio-protective effect via inhibition of cardiomyocyte apoptosis. Moreover, ICER is ubiquitinated and degraded by CHIP and ERK5 activation enhances CHIP ubiquitin ligase activity, subsequent ICER and FoxO1 degradation, and inhibits both cardiomyocyte apoptosis and autophagy. Since CHIP knockout mice (KO) showed increased myocyte apoptosis and autophagy after pressure overlaod, our working hypothesis is that ERK5-mediated Ub ligase CHIP activation is a key modulator of ICER and FoxO1 protein degradation and protects cardiomyocytes from both apoptosis and autophagy after MI in DM. Activation of CHIP-mediated ubiquitination is not the only downstream target of ERK5 activation, and there are several downstream molecules affected by ERK5 likely to impact MI injury. In this resubmission, we added a study on peroxisome proliferator-activated receptor (PPAR) 4 since ERK5 regulates PPAR4 transactivation in a CHIP-independent manner providing us with a platform to study CHIP-dependent vs. independent signaling in ERK5-mediated cardio-protection. Understanding the role and molecular mechanisms of ERK5-CHIP-mediated ICER and FoxO1 degradation and subsequent cardio-protection should provide insight into the reasons for poor cardiac recovery after MI in DM and possibly reveal a novel therapeutic target. The significance lies in the novel hypothesis on the role of the Ub-ligase CHIP in regulating both apoptosis and autophagy, and the proposed mechanistic study of a highly clinically relevant problem.